全麻药物通过内源性大麻素系统调节SCN-DMH-POA环路可塑性导致全麻后睡眠障碍的机制研究

全麻后睡眠障碍严重影响术后康复，但其发生机制不清。我们前期研究发现内源性大麻素系统（ECS）可通过逆行方式调节短程突触可塑性影响全麻觉醒。且ECS也是调节睡眠结构的重要系统，可能是调控生物钟与下游睡眠-觉醒核团的重要闸门。目前认为全麻后生物钟调控的核心脑区视交叉上核（SCN）的节律表达受到影响。我们预实验证实阻断SCN的下游核团背内侧下丘脑（DMH）的ECS，可显著改善全麻后睡眠障碍，且全麻可诱导DMH区GABA能神经元产生LTD。由此我们推测，全麻可通过激活ECS，诱发DMH区GABA能神经元产生LTD，进而长时程调控SCN-DMH-POA（视前区）的突触可塑性，导致了全麻后睡眠障碍。本项目拟应用多种模式动物、化学遗传学等技术，探索全麻通过ECS长期影响突触可塑性的作用及其对睡眠的影响，为揭示全麻后睡眠障碍的神经机制提供重要的实验依据和理论基础，也为临床干预提供新的治疗靶点和药物备选。

Sleep disturbance often occurs after general anesthesia, and its occurrence is harmful for postoperative recovery. So far, the mechanism of sleep disturbance after general anesthesia remains unclear. Our previous study have confirmed that general anesthesia could activate the endocannabinoid system (ECS), and the endocannabinoids could combined with Type 1 cannabinoid receptor (CB1R) to influence the emergence from general anesthesia through the activity-dependent retrograde regulation of synaptic transmission. Moreover, ECS plays an important role in regulation of sleep structure. As well, ECS intertwined with the circadian rhythm. The most of the molecules of ECS show diurnal changes, and cannabinoids affect sleep-wakefulness rhythm directly, indicating ECS serves as a link between circadian regulator (the intrinsic clock of the suprachiasmatic nucleus, SCN) and the physiological processes that affect. After general anesthesia, the level of circadian gene and protein in the SCN altered. Moreover, our preliminary experiments found that blockade of the CB1R in the dorsomedial hypothalamus (DMH), which is the important downstream nucleus of SCN, can significantly improve the sleep disturbance after general anesthesia. The underlying mechanism may be the endocanabinoids dependent long term depression(LTD) of the GABAergic neurons in the DMH induced by the isoflurane incubation. Therefore, we speculated that general anesthesia could activate the ECS to induce LTD in the GABAergic neurons in the DMH, and then regulate the synaptic plasticity of SCN-DMH-POA (preoptic area) in a long period, leading to sleep disturbance after general anesthesia. In the future, a variety of knock-in mutant mice combined with chemogenetics technique will be applied to explore how general anesthesia influence the postoperative sleep through regulating of synaptic plasticity by ECS in a long term. This study is aimed to provide important experimental basis and theoretical foundation for sleep disturbance after general anesthesia, and to represent a new therapeutic target and drug candidates for clinical intervention of sleep disturbance after general anesthesia.